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Biomedical subjects

A Aguzzi

Publications and source records attributed to A Aguzzi.

At least 145 records · Page 8Linked to original sources
PubMed1997

Mouse model to study the replication of primate foamy viruses.

A mouse model was developed to study the virus-host interaction of molecularly cloned human foamy virus (HFV) in vivo. The infectious process was analysed in two mouse strains, CBA/Ca and C57BL/6J, over a period of 24 weeks by PCR on DNAs from various animal tissues; virus serology was examined by immunoblotting. The infection persisted in both mouse strains and did not induce clinical symptoms. Upon infection of adult CBA/Ca mice HFV became detectable by PCR in an increasing number of organs over time. In contrast, in C57BL/6J mice, after an initial phase of dissemination, viral DNA sequences were found only in a few organs. Interestingly, the different course of infection was accompanied by differences in the antiviral immune response. In particular, C57BL/6J mice were high responders with respect to antibodies to the viral Bet protein, while CBA/Ca mice were low responders.

Animals↗
PubMed1997

The spectrum of transmissible spongiform encephalopathies.

Since the first description by A.M. Jakob and H.G. Creutzfeldt, five human diseases have been identified as transmissible spongiform encephalopathies (TSE). The disease bearing these authors' name, Creutzfeldt-Jakob disease (CJD) occurs sporadically, may be transmitted and has a genetic basis in 10-15% of all cases. Genetic diseases are the Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. The latest form of CJD in humans, variant CJD (vCJD), was first described in 1996 and may be considered as evidence for a link between human TSEs and those in the animal kingdom. The putative agent of all TSEs is a proteinaceous infectious agent or prion. The gene for the physiological isoform of this protein (prion related protein or PrPc)-is encoded on the short arm of chromosome 20 in humans. The role of the physiological isoform of PrPc is unknown. The physiological isoform PrPc is protease-sensitive and thus designated as PrP-sen, while the pathological isoform is protease-resistant and thus called PrP-res. The pathological isoform PrP-res is invariably associated with TSEs and has given rise to the term prion diseases. PrP-sen and PrP-res have an identical amino acid sequence and have identical posttranslational modifications as assessed by currently available methodology but differ in their tertiary and quaternary structure. These structural differences are thought to be propagated by interaction of PrP-res with PrP-sen, appear to be governed by the polymorphism of PrPc and have been shown to be invariably associated with disease. PrP-sen has a high content of alpha-helical structures, PrP-res consists predominantly of beta-pleated sheets. These physicochemical characteristics of PrP-res cause it to behave like amyloid. The neuropathological hallmarks of TSEs or prion diseases are spongiform change, astrocytic gliosis, neuronal loss and PrP-positive plaques. A nucleic acid has never consistently been shown in any TSE. Diagnosis of TSE can be reliably made only postmortem.

Animals↗
PubMed1997

Late glial swelling after acute cerebral hypoxia-ischemia in the neonatal rat: a combined magnetic resonance and histochemical study.

Secondary brain damage after transient cerebral hypoxia-ischemia (HI) is caused by a cascade of cellular events. In this study, complementary methods of magnetic resonance imaging and histochemistry were used to investigate the formation of cytotoxic and vasogenic edema during secondary brain damage induced by transient HI in 7-d-old rats. To elicit injury, 21 rats underwent right common carotid artery ligation followed by 1.5 h of 8% O2 exposure. Sequential apparent diffusion coefficient (ADC) and transversal relaxation time (T2) weighted magnetic resonance imaging were recorded for up to 3 d in 13 7-d-old rats. Eight animals were killed at various intervals between the end of HI and 21 h of recovery to perform histochemical assays using neuronal and astrocytic markers. Changes of the ADC revealed a biphasic function for the evolution of cytotoxic edema during the recovery period. At the end of HI, the ADC in the ipsilateral cortex was significantly decreased. Upon reoxygenation, it returned transiently to normal followed by a secondary, although less pronounced, decline after 8-48 h. After this, the ADC rose steadily. From 8 h of recovery, the proportion of vasogenic edema steadily increased as indicated by the T2 prolongation. At 21 h, the majority of glial cells showed immunoreactivity for glial fibrillary acidic protein and were of larger size, whereas the neurons were apoptotic. These results indicate that the delayed cerebral injury is accompanied by late glial swelling in conjunction with an enlarged interstitial space due to cell damage.

Animals↗
PubMed1997

MR differentiation of adamantinous and squamous-papillary craniopharyngiomas.

PURPOSE: To determine MR criteria for differentiating adamantinous from squamous-papillary craniopharyngiomas. METHODS: The MR imaging features of 42 histologically proved craniopharyngiomas (25 adamantinous, 15 squamous-papillary, and two mixed subtypes) were examined with multiplanar T2-weighted and noncontrast and contrast-enhanced T1-weighted imaging. Differences in the mR features of both subtypes were evaluated retrospectively. RESULTS: The adamantinous craniopharyngioma is a mixed solid-cystic or mainly cystic lobulated suprasellar or intrasellar/suprasellar tumor occurring in children and adults, typically with large nonenhancing hyperintense cysts on T1-weighted images. The squamous-papillary craniopharyngioma is a predominantly solid or mixed solid-cystic suprasellar tumor occurring in adults, appearing as a hypointense cyst on noncontrast T1-weighted images. Calcifications and recurrent tumors are more often observed in adamantinous tumors but can be seen in squamous-papillary tumors as well. Statistically significant parameters useful for differentiating the two tumor subtypes are the encasement of vessels, the lobulated shape, and the presence of hyperintense cysts in adamantinous tumors, and the round shape, the presence of hypointense cysts, and the predominantly solid appearance in squamous-papillary tumors. CONCLUSION: Craniopharyngiomas can be divided into two clinically, histologically different subtypes, which suggests a different pathogenesis of these two types of tumor.

Adolescent↗
PubMed1997

[Molecular pathogenesis of spongiform encephalopathies].

The understanding of the pathogenesis of transmissible spongiform encephalopathies (TSE) has advanced most significantly in the last forty years, and some scientists even feel that this group of diseases now ranks among the best understood neurodegenerative conditions. On the other hand, the research on TSE has led to several unexpected and sometimes amazing findings, which have often elicited passionate controversies. Although the human forms of these diseases are rare, the epidemic proportions of the bovine spongiform encephalopathy (BSE) forces us to urgently reconsider the question of transmissibility to humans. The present review article summarizes some of the current hypotheses about the nature of the infectious agent and about the pathogenesis of the damage in the central nervous system. In particular we discuss transgenic and knockout models which, in combination with organ transplantation techniques, are proving invaluable in the elucidation of the pathogenesis of these diseases.

Animals↗
PubMed1996

Normal host prion protein (PrPC) is required for scrapie spread within the central nervous system.

Mice devoid of PrPC (Prnp%) are resistant to scrapie and do not allow propagation of the infectious agent (prion). PrPC-expressing neuroectodermal tissue grafted into Prnp% brains but not the surrounding tissue consistently exhibits scrapie-specific pathology and allows prion replication after inoculation. Scrapie prions administered intraocularly into wild-type mice spread efficiently to the central nervous system within 16 weeks. To determine whether PrPC is required for scrapie spread, we inoculated prions intraocularly into Prnp% mice containing a PrP-overexpressing neurograft. Neither encephalopathy nor protease-resistant PrP (PrPSc) were detected in the grafts for up to 66 weeks. Because grafted PrP-expressing cells elicited an immune response that might have interfered with prion spread, we generated Prnp% mice immunotolerant to PrP and engrafted them with PrP-producing neuroectodermal tissue. Again, intraocular inoculation did not lead to disease in the PrP-producing graft. These results demonstrate that PrP is necessary for prion spread along neural pathways.

Animals↗
PubMed1996

Impaired differentiation of Schwann cells in transgenic mice with increased PMP22 gene dosage.

An intrachromosomal duplication containing the PMP22 gene is associated with the human hereditary peripheral neuropathy Charcot-Marie-Tooth disease type 1A, and PMP22 overexpression as a consequence of increased PMP22 gene dosage has been suggested as causative event in this frequent disorder of peripheral nerves. We have generated transgenic mice that carry additional copies of the pmp22 gene to prove that increased PMP22 gene dosage is sufficient to cause PNS myelin deficiencies. Mice carrying approximately 16 and 30 copies of the pmp22 gene display a severe congenital hypomyelinating neuropathy as characterized by an almost complete lack of myelin and marked slowing of nerve conductions. Affected nerves contain an increased number of nonmyelinating Schwann cells, which do not form onion bulbs but align in association with axons. The mutant Schwann cells are characterized by a premyelination-like state as indicated by the expression of embryonic Schwann cell markers. Furthermore, continued Schwann cell proliferation is observed into adulthood. We hypothesize that Schwann cells are impaired in their differentiation into the myelinating phenotype, leading to a disorder comparable to severe cases of hereditary motor and sensory neuropathies. Our findings, combined with the analysis of heterozygous and homozygous PMP22-deficient mice, indicate that aberrant pmp22 gene copy numbers cause various forms of myelination defects.

Animals↗
PubMed1996

Brain cell type specificity and gliosis-induced activation of the human cytomegalovirus immediate-early promoter in transgenic mice.

Human cytomegalovirus (HCMV) can cause debilitating, sometimes fatal, opportunistic infections in congenitally infected infants and in immunodeficient individuals such as patients with the acquired immunodeficiency syndrome (AIDS). Molecular mechanisms that determine cell type specificity of HCMV infection and latency are poorly understood. We recently described a transgenic mouse model for analysis of HCMV major immediate-early (IE) promoter regulation and showed that sites of IE promoter activity during murine embryogenesis correlate with known target tissues of congenital HCMV infection in human fetuses (Koedood et al., 1995). Among various permissive human tissues, the brain is a site where HCMV infections can be devastating. Here, we have used immunohistochemical double-labeling analysis to identify specific cell types with HCMV-IE promoter activity in brains of transgenic mice at several postnatal stages. IE promoter activity was restricted to some endothelial cells, ependymal cells, choroid plexus epithelia, and neurons at discrete locations in the forebrain, brainstem, and cerebellum. Endothelial cells and neurons with activity were proportionately more abundant in neonatal than in adult brains. Although the IE promoter was normally silent in most astrocytes, activity was strongly induced in reactive astrocytes in response to a neocortical stab lesion. The findings support a model, consistent with clinical literature on HCMV encephalitis, whereby tissue damage and gliosis caused by HCMV infection of endothelial and ependymal cells progressively renders adjacent permissive neurons and reactive astrocytes accessible to infection. This transgenic model system should facilitate identification of factors that regulate the HCMV IE promoter with regard to infection permissivity and reactivation from latency.

Animals↗
PubMed1996

Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie.

The 'protein only' hypothesis postulates that the prion, the agent causing transmissible spongiform encephalopathies, is PrP(Sc), an isoform of the host protein PrP(C). Protease treatment of prion preparations cleaves off approximately 60 N-terminal residues of PrP(Sc) but does not abrogate infectivity. Disruption of the PrP gene in the mouse abolishes susceptibility to scrapie and prion replication. We have introduced into PrP knockout mice transgenes encoding wild-type PrP or PrP lacking 26 or 49 amino-proximal amino acids which are protease susceptible in PrP(Sc). Inoculation with prions led to fatal disease, prion propagation and accumulation of PrP(Sc) in mice expressing both wild-type and truncated PrPs. Within the framework of the 'protein only' hypothesis, this means that the amino-proximal segment of PrP(C) is not required either for its susceptibility to conversion into the pathogenic, infectious form of PrP or for the generation of PrP(Sc).

Amino Acid Sequence↗
PubMed1996

Analysis of the determinants of neurotropism and neurotoxicity of HFV in transgenic mice.

The Bel-1 protein of human foamy virus (HFV) is a transactivator acting on the U3 region of the long terminal repeat and on an internal promoter (IP) immediately upstream of the bel genes. An HFV transgene called delta gpe, containing both promoters and all bel genes, is expressed in the central nervous system and induces neurodegeneration in mice. To dissect the role of individual promoters and bel genes on transgene expression and neurotoxicity we generated transgenic mice with a construct termed pL-bel1, which lacks the IP and the ancillary genes except bel-1. L-bel1 mice transcribed the HFV transgene in more tissues than delta gpe mice, suggesting that CNS specificity is dictated by cis-acting elements not present in the pLbel-1 construct. Unlike delta gpe mice, L-bel1 mice did not develop neurodegenerative changes and did not show induction of nitric oxide synthase expression, although both strains expressed Bel-1 in the brain. Therefore, Bel-1 expression is not sufficient for neurotoxicity. Our results suggest that Bet, a fusion protein between bel-1 and bel-2 which is highly expressed in delta gpe but not in L-bel1 mice, is a candidate for neurotoxicity.

Animals↗
PubMed1996

Normal host prion protein necessary for scrapie-induced neurotoxicity.

Accumulation of the prion protein PrPSc, a pathological and protease-resistant isoform of the normal host protein PrPC, is a feature of prion disease such as scrapie. It is still unknown whether scrapie pathology comes about by neurotoxicity of PrPSc, acute depletion of PrPC, or some other mechanism. Here we investigate this question by grafting neural tissue overexpressing PrPC into the brain of PrP-deficient mice which are scrapie-resistant and do not propagate infectivity. After intracerebral inoculation with scrapie prions, the grafts accumulated high levels of PrPSc and infectivity and developed the severe histopathological changes characteristic of scrapie. Moreover, substantial amounts of graft-derived PrPSc migrated into the host brain. Even 16 months after inoculation no pathological changes were seen in PrP-deficient tissue, not even in the immediate vicinity of the grafts. Therefore, in addition to being resistant to scrapie infection, brain tissue devoid of PrPC is not damaged by exogenous PrPSc.

Animals↗
PubMed1996

Mice homozygous for a modified beta-amyloid precursor protein (beta APP) gene show impaired behavior and high incidence of agenesis of the corpus callosum.

The amyloid precursor protein (beta APP) gene of the mouse was disrupted by homologous recombination; however, contrary to expectation, brain and other tissues still contained beta APP-specific RNA, albeit at a level 5-10 fold lower than wild-type and lacking the disrupted exon, which had been spliced out. The brain contained shortened beta APP-specific protein at a low level. Mutant mice were severely impaired in spatial learning and exploratory behavior and showed increased incidence of agenesis of the corpus callosum.

Agenesis of Corpus Callosum↗